Biological design — a neglected art

I ought now, perhaps, to offer a summary of what I have been trying to convey in this lecture — but I am haunted by the failure which attended an effort, by an eminent scholar of this city, to do something of the same kind many years ago. Sir John Sheppard, Provost of King's, once gave a public lecture during one of the University's ceremonial gatherings. His subject was the Trojan War. The large audience sat spellbound in admiration of his depth of insight, breadth of knowledge and grasp of detail. As he was leaving after the meeting, a young man came up to him and explained that he was a graduate studuent engaged in research on the economic consequences of the Trojan War. He had, however, been spellbound by the lecture and had been too engrossed to write anything down. Would Sir John be so kind as to lend him his notes so that he could make a summary of the lecture? “My dear chap”, said Sheppard, “I'd be delighted; here are my notes — use them as you wish and let me have them back whenever they have served your purpose”. So saying he handed the young man a postcard on which was written: Agamemnon — Achilles — Agamemnon.I hope that members of the audience won't mind if I leave them to make their own summary of my remarks to which they have listened so patiently this evening.     

Can we rationally design promiscuous drugs?

Structure-based drug design is now used widely in modern medicinal chemistry. The application of structural biology to medicinal chemistry has heralded the "rational drug design" vision of discovering exquisitely selective ligands. However, recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design. By combining advances in chemoinformatics and structural biology, it might be possible to rationally design the next generation of promiscuous drugs with polypharmacology.     

What is wrong with intelligent design?

This article reviews two standard criticisms of creationism/intelligent design (ID)): it is unfalsifiable, and it is refuted by the many imperfect adaptations found in nature. Problems with both criticisms are discussed. A conception of testability is described that avoids the defects in Karl Popper's falsifiability criterion. Although ID comes in multiple forms, which call for different criticisms, it emerges that ID fails to constitute a serious alternative to evolutionary theory.     

What is the protein design alphabet?

Selecting a protein sequence that corresponds to a specific three-dimensional protein structure is known as the protein design problem. One principal bottleneck in solving this problem is our lack of knowledge of precise atomic interactions. Using a simple model of amino acid interactions, we determine three crucial factors that are important for solving the protein design problem. Among these factors is the protein alphabet-a set of sequence elements that encodes protein structure. Our model predicts that alphabet size is independent of protein length, suggesting the possibility of designing a protein of arbitrary length with the natural protein alphabet. We also find that protein alphabet size is governed by protein structural properties and the energetic properties of the protein alphabet units. We discover that the usage of average types of amino acid in proteins is less than expected if amino acids were chosen randomly with naturally occurring frequencies. We propose three possible scenarios that account for amino acid underusage in proteins. These scenarios suggest the possibility that amino acids themselves might not constitute the alphabet of natural proteins.     

LCA in architectural design—a parametric approach

Purpose

Life cycle assessment (LCA) has not been widely applied in the building design process because it is perceived to be complex and time-consuming. There is a high demand for simplified approaches that architects can use without detailed knowledge of LCA. This paper presents a parametric LCA approach, which allows architects to efficiently reduce the environmental impact of building designs.

Methods

First, the requirements for design-integrated LCA are analyzed. Then, assumptions to simplify the required data input are made and a parametric model is established. The model parametrizes all input, including building geometry, materials, and boundary conditions, and calculates the LCA in real time. The parametric approach possesses the advantage that input parameters can be adjusted easily and quickly. The architect has two options to improve the design: either through manually changing geometry, building materials, and building services, or through the use of an optimization solver. The parametric model was implemented in a parametric design software and applied using two cases: (a) the design of a new multi-residential building, and (b) retrofitting of a single-family house.

Results and discussion

We have successfully demonstrated the capability of the approach to find a solution with minimum environmental impact for both examples. In the first example, the parametric method is used to manually compare geometric design variants. The LCA is calculated based on assumptions for materials and building services. In the second example, evolutionary algorithms are employed to find the optimum combination of insulation material, heating system, and windows for retrofitting. We find that there is not one optimum insulation thickness, but many optima, depending on the individual boundary conditions and the chosen environmental indicator.

Conclusions

By incorporating a simplified LCA into the design process, the additional effort of performing LCA is minimized. The parametric approach allows the architect to focus on his main task of designing the building and finally makes LCA practically useful for design optimization. In the future, further performance analysis capabilities such as life cycle costing can also be integrated.

     

Mammalian sex chromosomes: design or accident?

Mammalian sex chromosomes evolved (and are still evolving) from a homomorphic pair by the progressive loss of active genes from the Y chromosome. Among the changes that have accompanied this differentiation, it is difficult to determine causes, effects and correlates. Comparative studies suggest that the choice of a gene, and thus a chromosome pair, to control the sex-determining pathway may be quite arbitrary, and that sex chromosomes and sex-determining genes are more likely to be the products of random changes than the products of selection for function.     

Probing linker design in citric acid–ciprofloxacin conjugates

A series of structurally related citric acid–ciprofloxacin conjugates was synthesised to investigate the influence of the linker between citric acid and ciprofloxacin on antibacterial activities. Minimum inhibitory concentrations (MICs) were determined against a panel of reference strains and clinical isolates of bacteria associated with infection in humans and correlated with the DNA gyrase inhibitory activity. The observed trend was rationalised by computational modelling.     

Structure-guided design of α-amino acid-derived Pin1 inhibitors

The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of α-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC₅₀ <100 nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10–50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.     

Genetic design automation: engineering fantasy or scientific renewal?

The aim of synthetic biology is to make genetic systems more amenable to engineering, which has naturally led to the development of computer-aided design (CAD) tools. Experimentalists still primarily rely on project-specific ad hoc workflows instead of domain-specific tools, which suggests that CAD tools are lagging behind the front line of the field. Here, we discuss the scientific hurdles that have limited the productivity gains anticipated from existing tools. We argue that the real value of efforts to develop CAD tools is the formalization of genetic design rules that determine the complex relationships between genotype and phenotype.     

Should we take measurements at an intermediate design point?

It is well known that, for estimating a linear treatment effect with constant variance, the optimal design divides the units equally between the two extremes of the design space. If the dose-response relation may be nonlinear, however, intermediate measurements may be useful in order to estimate the effects of partial treatments. We consider the decision of whether to gather data at an intermediate design point: do the gains from learning about nonlinearity outweigh the loss in efficiency in estimating the linear effect? Under reasonable assumptions about nonlinearity, we find that, unless sample size is very large, the design with no interior measurements is best, because with moderate total sample sizes, any nonlinearity in the dose-response will be difficult to detect. We discuss in the context of a simplified version of the problem that motivated this work-a study of pest-control treatments intended to reduce asthma symptoms in children.     

Computational design and structure–property relationship studies on heptazines

This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting systematic structure–property relationships. Molecular structures with diverse energetic substituents at varying positions in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm⁻³, and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics. The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas generators and smoke-free pyrotechnic fuels as they are rich in nitrogen content.     

Advances in helminth immunology: optimism for future vaccine design?

Intestinal helminths infect approximately 2 billion people worldwide. Worm burdens correlate with disease morbidity and children generally harbor the largest numbers. The majority of intestinal helminths do not replicate within their host, and worm burdens increase through constant reinfection. Current strategies of worm control involve drug administration to school-aged children. Yet the rapid rate of reinfection and the appearance of drug resistant strains in livestock raise concerns over the sustainable nature of this strategy. A combined strategy of drug treatment for the expulsion of adult worms and vaccination designed to halt reinfection would offer the most effective means of control. Before successful vaccines can be developed our knowledge of the initiation and implementation of host immunity must be improved.     

Survey says? A primer on web-based survey design and distribution

The Internet has changed the way in which we gather and interpret information. Although books were once the exclusive bearers of data, knowledge is now only a keystroke away. The Internet has also facilitated the synthesis of new knowledge. Specifically, it has become a tool through which medical research is conducted. A review of the literature reveals that in the past year, over 100 medical publications have been based on Web-based survey data alone. Because of emerging Internet technologies, Web-based surveys can now be launched with little computer knowledge. They may also be self-administered, eliminating personnel requirements. Ultimately, an investigator may build, implement, and analyze survey results with speed and efficiency, obviating the need for mass mailings and data processing. All of these qualities have rendered telephone and mail-based surveys virtually obsolete. Despite these capabilities, Web-based survey techniques are not without their limitations, namely, recall and response biases. When used properly, however, Web-based surveys can greatly simplify the research process. This article discusses the implications of Web-based surveys and provides guidelines for their effective design and distribution.     

Hot spot-based design of small-molecule inhibitors for protein–protein interactions

Protein–protein interactions (PPIs) are important targets for the development of chemical probes and therapeutic agents. From the initial discovery of the existence of hot spots at PPI interfaces, it has been proposed that hot spots might provide the key for developing small-molecule PPI inhibitors. However, there has been no review on the ways in which the knowledge of hot spots can be used to achieve inhibitor design, nor critical examination of successful examples. This Digest discusses the characteristics of hot spots and the identification of druggable hot spot pockets. An analysis of four examples of hot spot-based design reveals the importance of this strategy in discovering potent and selective PPI inhibitors. A general procedure for hot spot-based design of PPI inhibitors is outlined.     

Purine salvage in Leishmania: complex or simple by design?

Purine nucleotides function in a variety of vital cellular and metabolic processes including energy production, cell signaling, synthesis of vitamin-derived cofactors and nucleic acids, and as determinants of cell fate. Unlike their mammalian and insect hosts, Leishmania cannot synthesize the purine ring de novo and are absolutely dependent upon them to meet their purine requirements. The obligatory nature of purine salvage in these parasites, therefore, offers an attractive paradigm for drug targeting and, consequently, the delineation of the pathway has been under scientific investigation for over 30 years. Here, we review recent developments that reveal how purines flux in Leishmania and offer a potential 'Achilles' heel' for future validation.